Hydrophilic microporous membrane for drug delivery devices and method for preparing same

ABSTRACT

Articles having a complex geometric configuration have hydrophilicity imparted to at least a portion of surfaces of the articles while substantially retaining the complex geometric configuration. The hydrophilicity is imparted by an extremely thin, self-interlocking shell of tactic, hydrophilic poly(vinyl alcohol) enveloping the surfaces. A tactic poly(vinyl alcohol) precursor applied to surfaces of the supporting structure is reacted in situ on the surfaces with a hydrolysis reagent to prepare the tactic, hydrophilic poly(vinyl alcohol) shell. The article having the hydrophilic shell is highly resistant to solvent washout. Hydrophilicity and hydrophobicity can be reversibly provided on regio-specific surfaces of the article. Articles in the form of membranes useful as drug delivery device components are also described.

RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.08/122,807 filed Sep. 16, 1993, now U.S. Pat. No. 5,443,727, which is acontinuation of U.S. patent application Ser. No. 07/775,969 filed Nov.8, 1991, abandoned, which is a continuation-in-part of U.S. patentapplication Ser. No. 07/605,834 filed Oct. 30, 1990, abandoned, and acontinuation-in-part of U.S. patent application Ser. No. 07/605,754filed Oct. 30, 1990, abandoned, and a continuation-in-part of U.S.patent application Ser. No. 07/605,948 filed Oct. 30, 1990, abandoned,and a continuation-in-part of Ser. No. 07/605,921 filed Oct. 30, 1990,abandoned, and a continuation-in-part of Ser. No. 07/605,828 filed Oct.30, 1990, abandoned, and a continuation-in-part of Ser. No. 07/605,757filed Oct. 30, 1990, abandoned. All prior related applications areincorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to articles such as membranes having an extremelythin hydrophilic polymeric shell about surfaces of the article whilesubstantially retaining the geometric configuration of the article, theuse of hydrophilic microporous membranes in and the method of preparingsuch articles.

BACKGROUND OF THE INVENTION

Many polymeric materials are hydrophobic. When such materials are formedinto films, beads, membranes or the like, their hydrophobic natureprevents or inhibits "wetting" by water.

When used to describe a surface, the term "hydrophobic" means that wateron that surface has a contact angle of greater than ninety degrees. Bycontrast, the term "hydrophilic" applies to those polymeric surfaceswhich have a contact angle of less than ninety degrees.

While hydrophobic materials are well known in the art and easilyprepared, their usefulness in many processes and products is severelyrestricted by their hydrophobicity. There have been numerous priorattempts to render a hydrophobic material hydrophilic in order to beuseful in processes where water is present and must "wet" the surface ofthe material.

Several efforts have concentrated in rendering hydrophilic a poroushydrophobic polymeric membrane. Despite the low cost of preparation ofsuch hydrophobic materials in the form of porous membranes, suchmembranes are not useful as membranes in aqueous systems becausecapillary forces at the pores of such hydrophobic materials prevent thewetting of the pores by water, aqueous solutions, or other high surfacetension organic solutions.

Treatment of the surfaces of hydrophobic materials, such as porousmembranes, made from polyolefins has been attempted using surfactantcoatings such as the silicone glycol copolymer disclosed in U.S. Pat.No. 3,853,601 (Taskier) or the nonionic alkylphenoxypoly(ethyleneoxy)ethanol surfactant disclosed in U.S. Pat. No. 4,501,793(Sarada), or a copolymer coating having hydrophilic monomeric units andhydrophobic monomeric units such as an ethylene-vinyl alcohol copolymerdisclosed in European Patent Office Publication No. 0 023 459 (Nitadoriet al.). Unfortunately, such surfactant treatments to the surfaces ofhydrophobic materials may not be permanent due to the washing away ofsuch surface coatings by water or a variety of organic solventsincluding those used to form the coating on the supporting hydrophobicarticle. Also, surfactants are commonly known to denature enzymes. See,for example, Molecular Cell Biology, J. Darnell et al. Fds., ScientificAmerican Books, 232, (1986).

Another approach taken in the art is the adsorption of a hydrophilicpolymer on a hydrophobic substrate, as disclosed in U.S. Pat. No.4,794,002 and corresponding European Patent Office Publication 0 221 046(Henis et al.). A modifying polymer may be adsorbed onto the surfaces ofa polysulfone or a polyethersulfone from an aqueous solution of themodifying polymer. But the modifying polymer can be removed withdetergent solutions and the like.

Relatively permanent hydrophilic coatings on hydrophobic microporousfilms have been attempted by further treatment of chemical cross-linkingof or ionizing radiation directed against the coating. U.S. Pat. No.4,346,142 (Lazear) discloses an ionizing radiation process. U.S. Pat.No. 4,776,959 (Kasai et al.) discloses thermally curing a waterinsoluble vinyl alcohol-vinyl acetate copolymer onto a porous membrane.U.S. Pat. No. 4,753,725 (Linder et al.) discloses semipermeablecomposite membranes made by reacting PVA/PVA-copolymer films with amonomeric organic compound containing at least two functional groups, alinear or branched polyfunctional oligomer or polymer, and a compoundcontaining cross-linking and ionizable groups. Japanese Publ. No.JP62-14903 (Ohtani et al.) describes using a solution containing acompound having ester side chains and a crosslinking agent to thermallycrosslink the ester side chains to hydroxyl or carboxyl reactive siteson the hydrophobic polymer.

Others have attempted to apply hydrophilic poly(vinyl alcohol) directlyto the hydrophobic polymer membrane. Japanese Publ. No. JP62-277106(Ikehara et al.) describes the ionic cross-linking of a poly(vinylalcohol) on a microporous polymer substrate from a water-solublepoly(vinyl alcohol) polymer containing an inorganic alkaline compound.While poly(vinyl alcohol) has excellent hydrophilicity, processingdifficulties are encountered when one attempts to coat hydrophilicpoly(vinyl alcohol) directly onto the hydrophobic membrane from a polaror aqueous solution.

Another has attempted to form hollow fiber microporous membranes withpoly(vinyl alcohol) chemically bonded to the surfaces of the hollowfiber membrane. U.S. Pat. No. 4,885,086 (Miura) discloses that a hollowfiber membrane is irradiated with ionizing radiations and then reactedwith vinyl acetate and hydrolyzed.

The attempts described in the art to provide a hydrophilic poly(vinylalcohol) coating are based on using atactic poly(vinyl alcohol), whichhas a low crystallinity content. It is believed that coatings based onatactic poly(vinyl alcohol) are more soluble in a range of solvents andaqueous fluids and consequently the coatings are more readily washedaway, particularly when contacted with solvents miscible with thesolvents used to bring the hydrophilic material in contact with thehydrophobic membrane.

It is possible to produce poly(vinyl alcohol) which is not atactic.Preparation and the properties of syndiotactic and isotactic poly(vinylalcohol) have been described in Harris et al., Journal of PolymerScience: Part A-1, Vol. 4, 665-677 (1966), describing the preparation ofsyndiotactic poly(vinyl alcohol) from poly(vinyl trifluoroacetate) andisotactic poly(vinyl alcohol) from poly(vinyl tert-butyl ether).Further, the production of poly(vinyl trifluoroacetate) as a precursorfor syndiotactic poly(vinyl alcohol) has been described in Haas et al.,Journal of Polymer Science, Vol. 22, pgs. 291-302 (1956).

Prior uses of such tactic poly(vinyl alcohol) materials have includedthe preparation of ophthalmic articles, such as contact lenses andcoatings for such articles, from non-crosslinked poly(vinyl alcohol)copolymers hydrated to have controlled hydrogel properties and highstrength. Co-assigned, related U.S. Pat. Nos. 4,528,325; 4,618,649;4,693,939; 4,694,037; 4,780,514; 4,840,992; and 4,921,908 (Ofstead)disclose these copolymers and shaped articles, with U.S. Pat. No.4,693,939 disclosing these copolymers as coatings on articles.

Non-crosslinked crystallized poly(vinyl alcohol) coatings have beendisclosed for use with a variety of medical devices. European PatentPublication 0 370 657 (Ofstead) discloses a poly(vinyl alcohol) coatingon medical devices (such as catheter guidewires), which is prepared bycoating atactic poly(vinyl alcohol) on the device and then annealing thecoating to crystallize the poly(vinyl alcohol) to provide a slipperysurface.

However, the art of preparing crystallized poly(vinyl alcohol) hydrogelcoatings has failed to recognize that in many instances it is desirableto retain the particular geometric configuration of the article beingcoated. Crystallized poly(vinyl alcohol) which is capable of becoming ahydrogel in the presence of water can disrupt a complex geometricconfiguration of a supporting structure, such as by blocking the poresof a microporous membrane, if the coating applied to the supportingstructure is not carefully controlled.

Transdermal Drug Delivery Devices

Transdermal drug delivery devices provide an advantageous means fordelivering many therapeutic agents. The use of such devices avoids"first pass" metabolism by the liver, increases patient compliance, andprovides sustained delivery of the agent.

Some of the devices employ a microporous membrane to control the rate atwhich the therapeutic agent is delivered from the device to the skin.Other devices employ a microporous membrane to isolate the therapeuticagent in a reservoir.

However, the microporous membranes currently employed are hydrophobic.This hydrophobicity severely limits the utility of the membranes for usein transdermal delivery devices with a therapeutic agent which ishydrophilic. A hydrophobic membrane would block delivery of ahydrophilic therapeutic agent and would not release a therapeutic agentfrom isolation in a reservoir at the desired rate.

Hydrophobic microporous membranes would have broader utility in drugdelivery devices for the controlled delivery of hydrophilic therapeuticagents if the membranes could be rendered hydrophilic while stillretaining the geometric configuration of the membrane.

SUMMARY OF THE INVENTION

The present invention describes a supporting structure having a complexgeometric configuration and an extremely thin hydrophilic polymer shellwhich imparts hydrophilicity to the structure. The present inventionalso describes a method of providing such hydrophilicity whilesubstantially retaining the geometric configuration of the structure.

The present invention also provides a hydrophilic microporous drugdelivery membrane having an extremely thin hydrophilic polymer shellwhich imparts hydrophilicity to the microporous membrane withoutotherwise substantially altering the membrane.

The invention overcomes the deficiencies in the prior art by providing asupporting structure having a complex geometric configuration envelopedat at least a portion of its surfaces by an extremely thin,self-interlocking shell of tactic, hydrophilic homopolymer or copolymerof poly(vinyl alcohol) while substantially retaining the complexgeometric configuration of the supporting structure. The tacticpoly(vinyl alcohol) shell may be either syndiotactic or isotactic.

As used herein, "complex geometric configuration" refers to themultiplicity and types of surfaces of a supporting structure Whenobserved on a micron scale. The extremely thin shell of poly(vinylalcohol) On a supporting structure envelops the multiplicity of suchsurfaces without altering the type of such surfaces. Thus, thepoly(vinyl alcohol) shell imparts hydrophilicity to a supportingstructure while substantially retaining the complex geometricconfiguration of the supporting structure.

The multiplicity of surfaces of a supporting structure are enveloped bythe poly(vinyl alcohol) shell. "Envelop" means the shell entirelysurrounds each of the multiple surfaces and imparts hydrophilicitythereto. Integrity is imparted by the formation of crystallinecrosslinks within the shell, i.e., the formation of tie moleculesconnecting two or more crystallites. Thus, the shell isself-interlocking mechanically about the surfaces of the supportingstructure without substantial covalent, ionic, or van der Waalsinteraction with such surfaces.

The type of surfaces that a supporting structure may have may beexpressed in terms of Euclidean geometry, fractal geometry, or acombination of both.

A fractal is an object or process that cannot be represented byEuclidean geometry. With the complexity of natural shapes and surfacesbeing so jagged that they have more than two dimensions, fractalgeometry has become useful to analyze shapes so commonly found innature. (Van Nostrand's Scientific Encyclopedia Seventh Edition, VanNostrand Reinhold 1989, p. 1221.)

Euclidean surfaces may be planar, curved, or any other topography whichmay exhibit a Euclidean geometric configuration.

Fractal surfaces may be porous, tentacular, jagged, uneven, undulating,irregular, asymmetrical, or of any other topography which may exhibit anon-Euclidean geometric configuration.

For example, a porous membrane or bead may appear to have surfaces whichare planar or spherical, respectively, i.e., in a Euclidean geometricconfiguration. But at a micron scale, the membrane and bead have acomplex geometric configuration, because a precise examination of themultiplicity of surfaces shows a fractal, three dimensional terrainwhich defies Euclidean characterization. The pores of the membrane orbead are uneven, irregular, and unpatterned in all of the threedimensions Euclidean geometry measures. The fractal surfaces surroundingsuch pores generate a complex geometric configuration for the supportingfractal structure. The poly(vinyl alcohol) shell of the presentinvention envelops such fractal surfaces defining such pores but doesnot cover or fill such pores or otherwise convert the fractalconfiguration of the surfaces to a Euclidean configuration.

In another example, a non-woven web may appear to be flat and have aEuclidean geometric configuration. But at a micron scale, surfaces ofthe web are an unpatterned layering of strands which give the non-wovenweb a complex geometric configuration, even if the individual strandscomprising the web have a Euclidean geometric configuration. Thepoly(vinyl alcohol) shell of the present invention envelops the strandsof the web while substantially retaining the complexity of the surfacesand the fractal configuration of the non woven web.

The hydrophilic, polymeric shell enveloping the supporting structure is"extremely thin", on a scale of monolayers of polymer. "Extremely thin"means that the shell's monolayer dimension is such that it does notsubstantially clog, smooth, block, or swell in manner to appreciablyalter a supporting structure's complex geometry. Unlike a hydrogelcoating, which, upon exposure to water would swell and significantlyalter a geometric configuration of a supporting structure, theself-interlocking shell of poly(vinyl alcohol) of the articles of thepresent invention does not appreciably swell, substantially retainingthe complex geometry of the article.

A supporting structure such as a membrane may have a Bubble Point PoreSize (c.f. ASTM F-316) of about 0.01 to 20 μm. The present inventionfinds that an extremely thin shell of hydrophilic polymer having lessthan about an average of 100 Angstroms thickness forming a shell onfractal surfaces of the membrane reduces the effective pore size lessthan about 30 percent and desirably less than about 15 percent. Thecomplex geometric configuration of the supporting structure issubstantially retained.

Thus, the present invention allows the supporting structure to acquire ahydrophilic surface without altering its physical configuration.

The supporting structure has at least one surface in a complex geometricconfiguration which the poly(vinyl alcohol) shell may envelop.Nonlimiting examples of a supporting structure include films, porousmembranes, beads, woven and non-woven webs, spun threads, hollow porousfibers, and porous fibers. Nonlimiting examples of the composition ofthe supporting structure may be polymeric, ceramic, cellulosic, glassy,metallic, or carbonaceous.

A polymeric structure may be made from any useful and formable polymericmaterial which does not dissolve substantially in the presence ofsolvents used with precursors to make the shell. Nonlimiting examplesinclude without limitation, polyolefins (e.g., polyethylene andpolypropylene), polyhalo olefins (e.g., polytetrafluoroethylene andpolyvinylidene fluoride), nylon, polyesters (e.g., polyethyleneterephthalate), polysulfones, polyethersulfones,poly(2,6-dimethyl,4-phenylene oxide) and derivatives thereof,polyamides, polyimides, polyetherimides, or polymeric materialspreviously unavailable for forming hydrophilic polymeric structures.

The tactic, hydrophilic shell of a homopolymer or copolymer ofpoly(vinyl alcohol) is formed in-situ about complex, envelopablesurfaces of the supporting structure by hydrolysis (e.g., alcoholysis orammonolysis) of a tactic hydrophobic polymeric poly(vinyl alcohol)precursor with a hydrolysis reagent.

"Hydrolysis" means the cleaving of an ester or ether group in thepresence of a hydrolysis reagent to form an alcohol group.

The hydrophobic polymeric poly(vinyl alcohol) precursor can be anytactic poly(vinyl alcohol) precursor which forms a tactic homopolymer orcopolymer of poly(vinyl alcohol), including without limitation,homopolymers of vinyltrifluoroacetate and copolymers ofvinyltrifluoroacetate monomers and monomers having a vinylic grouptherein, homopolymers of vinyl tert-butyl ether monomers, and copolymersof vinyl tert-butyl ether monomers and monomers having a vinylic grouptherein. For purposes of describing this invention, references topoly(vinyl alcohol) shall include both a homopolymer of poly(vinylalcohol) and a copolymer of vinyl alcohol and another co-monomer.

The invention also overcomes problems confronted in the prior art byproviding a method for generating an extremely thin shell of tacticpoly(vinyl alcohol) about envelopable surface(s) of a supportingstructure. The method employs applying a tactic, polymeric poly(vinylalcohol) precursor to surfaces of the supporting structure, and thencausing, in-situ, a hydrolysis reaction to form a tactic, hydrophilicpoly(vinyl alcohol) shell enveloping such surfaces while retaining thecomplex geometric configuration of the supporting structure.

The hydrolysis reagent may be a reagent which causes the formation oftactic poly(vinyl alcohol), whether such reaction occurs in liquid orgaseous phase. Preferably, the hydrolysis reagent is a basic reagenthaving a pH greater than about 7.0. Suitable reagents include, but arenot limited to, dissolved or anhydrous ammonia, sodium hydroxide, sodiumcarbonate, and potassium hydroxide.

Many desirable articles having a hydrophilic polymeric shell thereon maybe made and used in accordance with the present invention. The articlemay take the form of porous membranes where fractal surfaces definepores and interstices in and through the membrane. The shell ofpoly(vinyl alcohol) does not substantially alter the complex geometricconfiguration of the membrane

A microporous membrane may be used as a layer in a drug delivery devicefor controlling the rate of delivery of a therapeutic agent through thedevice and to the skin of a patient or for isolating the therapeuticagent in a reservoir until use commences. Thus, the invention alsoprovides a drug delivery device comprising a hypoallergenic pressuresensitive adhesive layer, a therapeutic active agent and the hydrophilicmicroporous membrane contacting the adhesive layer and in communicationwith the therapeutic agent. The drug delivery device may employ thehydrophilic membrane between the skin and a reservoir containing thetherapeutic agent or may employ the membrane as a depot for atherapeutic agent.

The present invention provides a hydrophilic polymeric self-interlockingshell about surfaces of a supporting structure while substantiallyretaining the complex geometric configuration of the structure, and topermit that hydrophilized article to be used in aqueous systems or withorganic solvents without adversely affecting the hydrophilic polymericshell.

The present invention also provides a method for forming an extremelythin shell of tactic, hydrophilic poly(vinyl alcohol) about a supportingstructure, such as a microporous membrane, through the use of a tacticpoly(vinyl alcohol) precursor capable of being converted, in-situ, on atleast a portion of the complex surfaces of the supporting structure totactic poly(vinyl alcohol) while substantially retaining the complexgeometric configuration of the structure.

A feature of the invention is that the hydrophilic polymeric shell maybe prepared using readily available materials reacted at minimallyelevated temperatures and pressures.

It is another feature of the invention that the extremely thinhydrophilic polymeric shell of tactic hydrophilic poly(vinyl alcohol)envelops all outer surfaces of the supporting structure and anyavailable interior surfaces without blocking or clogging such pores orinterstices or otherwise substantially altering the complex geometricconfiguration of the supporting structure.

It is another feature of the invention to provide a tactic hydrophilicpoly(vinyl alcohol) shell on a supporting structure which has hydroxylreactive sites available for further reaction.

It is an advantage of the invention that articles produced according tothe present invention have a surface shell which is permanent in thepresence of aqueous systems or organic solvents, including thoseemployed during use of a hydrophilic article.

It is another advantage of the invention that the tactic, hydrophilicpoly(vinyl alcohol) shell provides increased mechanical strength to thepolymeric structure, thereby enhancing the stability and sturdiness ofan otherwise delicate film, membrane, web, or other structure whilesubstantially retaining the physical configuration of that structure.

For a greater appreciation of embodiments of the invention, a detaileddescription follows with reference to the drawing.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1a is a scanning electron photomicrograph of the outer surfaces ofa supporting structure made according to U.S. Pat. No. 4,539,256 withouta tactic, hydrophilic poly(vinyl alcohol) shell thereon.

FIG. 1b is a scanning electron photomicrograph of the outer surfaces ofa supporting structure with a tactic, hydrophilic poly(vinyl alcohol)shell thereon made according to the present invention.

FIG. 2a is a scanning electron photomicrograph of the outer andcross-sectional surfaces of a polymeric structure made according to U.S.Pat. No. 4,539,256 without a tactic, hydrophilic poly(vinyl alcohol)shell thereon.

FIG. 2b is a scanning electron photomicrograph of the outer andcross-sectional surfaces of a polymeric structure with a tactic,hydrophilic poly(vinyl alcohol) shell thereon made according to thepresent invention.

FIG. 3a is an illustration of a membrane microstructure which isenveloped by a poly(vinyl alcohol) shell.

FIG. 3b is an exploded view of another illustration of the envelopedpolymeric structure of FIG. 3a.

FIG. 4 illustrates a cross sectional view of a drug delivery device ofthe reservoir type.

FIG. 5 illustrates a cross sectional view of another embodiment of adrug delivery device of the reservoir type.

FIG. 6 is a cross sectional view of a drug delivery device of the depottype.

EMBODIMENTS OF THE INVENTION

Supporting Structure

The supporting structure may be composed of any individual orcombination of compositions of polymeric, ceramic, cellulosic, glassy,metallic, or carbonaceous materials. These materials may be eitherhydrophobic or hydrophilic in nature.

The supporting structure has a complex geometric configuration at amicron scale and may be formed according to known techniques intomembranes, films, woven and non-woven webs, beads, spun threads, porousfibers, porous hollow fibers, or any other three dimensionalconfiguration having a topography which permits the poly(vinyl alcohol)shell to envelop surface(s) of the structure in a self-interlockingfashion.

Non-limiting examples of the types of surfaces which can be envelopedinclude reticulated porous microstructures and tentacular outer surfacesof a structure.

Desirably, surfaces of any of these supporting structures provide agreater surface area per unit mass than that apparent from the grossEuclidean dimensions of the supporting structure. Many uses of articlesare dependent on providing a large surface area per unit mass. Thehydrophilic polymeric shell of the present invention impartshydrophilicity without reducing substantially the surface area of thesupporting structure.

Polymeric structures are preferred supporting structures. Of polymericstructures, porous membranes are preferred. More preferably, theseporous membranes are microporous.

The effective pore sizes of the structure may be at least several timesthe mean free path of flowing molecules, e.g., from about a nanometer toabout several micrometers. The porous membrane has a reticulated surfacestructure throughout its mass, which provides surface(s) for envelopingthe complex geometric configuration of the membrane with a tactic,hydrophilic, poly(vinyl alcohol) shell.

The polymeric structure may be made from any polymeric material whichmay be formed into a desired complex geometric configuration.

Non-limiting examples of the polymeric materials used to make polymericstructures are: polysulfones, polyethersulfones,poly(2,6-dimethyl-4-phenylene oxide) and derivatives thereof,polyamides, polyimides, polyetherimides, polyolefins, polyhalo olefins(especially polytetrafluoroethylene), polyesters, nylon, and the like.

Non-limiting examples of suitable polyolefins include (regardless ofmolecular weight) polyethylene, polypropylene, poly-3-methyl-1-butene,poly-4-methyl-1-pentene, copolymers of ethylene, propylene,3-methyl-1-butene, or 4-methyl-1-pentene with each other or with minoramounts of other olefins, e.g., copolymers of ethylene and propylene,copolymers of a major amount of 3- methyl-1-butene, and a minor amountof a straight chain n-alkene having from 2 to 18 carbon atoms such as1-octene, 1-hexadecene, and octadecene or other relatively long chainalkenes, as well as copolymers of 3-methyl-1-pentene, and any of thesame alkenes mentioned previously in connection with 3-methyl-1-butene.

A polyolefinic material may also include small amounts of othermaterials which may be copolymerized or blended therewith, but which donot substantially adversely affect the characteristics of thepolyolefinic material.

The material comprising the polymeric structure should have a weightaverage molecular weight greater than about 1000, and preferably greaterthan about 50,000, a melt index less than about 1200 grams/10 minutesand preferably less than about 10 grams/10 minutes as measured accordingto ASTM D 1238-82.

When the polymeric structure takes the form of a porous or microporousmembrane or other porous configuration, the polymeric structure shouldhave a porosity of from about 15 percent to about 99 percent, andpreferably from about 30 percent to about 95 percent. The porositymeasurements are made according to ASTM D-792.

When the polymeric structure takes the form of a membrane or otherporous configuration, the structure should have an effective pore sizein micrometers, measured according to ASTM F-316, of from about 0.01 μmto about 20 μm, and preferably from about 0.1 μm to about 1.2 μm.

Tactic, Hydrophilic Poly(vinyl Alcohol) Shell

The tactic, hydrophilic poly(vinyl alcohol) is prepared by the reactionof a tactic, polymeric poly(vinyl alcohol) precursor with a hydrolysisreagent. The tacticity of the poly(vinyl alcohol) ranges from about 50percent tactic triads to about 80 percent tactic triads using FluorineNMR spectroscopy methods. Pritchard et al., "Fluorine NMR Spectra ofPoly(vinyl Trifluoroacetate)" J. Poly. Sci. 4, 707-712 (1966),incorporated by reference herein, discloses calculation of triadtacticities for poly(vinyl alcohol) prepared by various methods.

The extremely thin shell of poly(vinyl alcohol) enveloping surface(s) ofa supporting structure is described in terms of monolayers of poly(vinylalcohol) on complex surfaces of a supporting structure. A "monolayer" isthe thickness of the smallest dimension of a crystalline unit cell ofpoly(vinyl alcohol), about 2.53 Angstroms. The poly(vinyl alcohol) shellmay comprise greater than an average of 10 monolayers to imparthydrophilicity to the complex geometric and often hydrophobic surfacesof a supporting structure.

The "extremely thin" self-interlocking shell of poly(vinyl alcohol)imparting hydrophilicity does not appreciably swell upon exposure towater to substantially alter the complex geometric configuration of asupporting structure.

Reference to an "average of" a number of monolayers compensates for thefact that these extremely thin shells are not of exact uniform thicknessthroughout the entire complex geometric configuration of the supportingstructure.

If the supporting structure is porous and it is desired not to block orclog such pores of a nominal 2 micron pore size, the poly(vinyl alcohol)shell may comprise from about an average of about 10 to about 4,000monolayers. Desirably, the poly(vinyl alcohol) shell may comprise fromabout an average of 10 to about an average of 400 monolayers. It ispresently preferred that the poly(vinyl alcohol) may comprise from aboutan average of 10 to about an average of 40 monolayers.

Based on the dimensions of pore size of a porous supporting structureand the monolayers of poly(vinyl alcohol) enveloping surfaces of thatsupporting structure, it is desirable to have a shell of tacticpoly(vinyl alcohol) occupy less than 30 percent of the pore sizeexisting in the supporting structure prior to forming such poly(vinylalcohol) shell. Preferably, the tactic poly(vinyl alcohol) occupies lessthan 15 percent of the original pore size.

The tactic, hydrophilic poly(vinyl alcohol) shell is relativelyinsoluble in water or highly polar organic solvents, or nonpolar organicsolvents. Such organic solvents include without limitation,dimethylsulfoxide, glycerol, ethylene glycol, and other solvents havinga solubility parameter differential from poly(vinyl alcohol) of greaterthan about 0.4 and desirably greater than about 0.6. The solubilityparameter δ (H) for poly(vinyl alcohol) is about 12.6. A tacticpoly(vinyl alcohol) shell of the present invention resists some washingsby solvents having solubility parameters of less than about 12.2 orgreater than about 13.0. Moreover, the tactic poly(vinyl alcohol) shellresists repeated washings by solvents having solubility parameters ofless than about 12.0 or greater than about 13.2. Solubility parametersfor solvents may be found in the Handbook of Chemistry and Physics, 60thEdition, Chemical Rubber Company. The tactic, hydrophilic poly(vinylalcohol) shell of the present invention resists washout by any of theabove-named solvents.

Desirably, the initial solubility of the hydrophilic poly(vinyl alcohol)shell when exposed to the above-named solvents is less than about 1 partper 100 parts of solvent at room temperatures and pressures with nomeasurable solubilization thereafter. Such relative insolubility of thepoly(vinyl alcohol) shell in water and polar and nonpolar organicsolvents provides continuing hydrophilicity of the article during usagein the presence of such solvents.

Polymeric Poly(vinyl Alcohol) Precursor

The poly(vinyl alcohol) precursor may be a tactic homopolymer ofvinyltrifluoroacetate, a tactic copolymer of vinyltrifluoroacetatemonomer and monomer(s) having a vinylic group therein, a tactichomopolymer of vinyl tert-butyl ether, or a tactic copolymer of vinyltert-butyl ether monomer and monomer(s) having a vinylic group therein.

The weight average molecular weight of the homopolymer or copolymers ofpoly(vinyltrifluoroacetate) range from about 50,000 to about 2,000,000and desirably range from about 500,000 to about 1,000,000. Desirably,the syndiotactic homopolymer or syndiotactic copolymer ofpoly(vinyltrifluoroacetate) is unbranched.

The weight average molecular weight of the homopolymer or copolymers ofpoly(vinyl tert-butyl ether) range from about 25,000 to about 60,000 anddesirably from about 35,000 to about 45,000.

Non-limiting examples of monomers having a vinylic group therein, usefulfor copolymerization to form the precursor, include vinyl esters havingup to six carbon atoms, vinyl ethers having up to eight carbon atoms,and disubstituted ethylenes (such as esters or anhydrides of lower alkyl(C₁ -C₄) substituted or unsubstituted dicarboxylic acids having up toeight carbon atoms). Of these possible monomers, maleic anhydride andvinyl acetate are preferred.

The presently preferred precursor is syndiotactic poly(vinyltrifluoroacetate) homopolymer.

The precursor typically is hydrophobic and is applied in relativelydilute solution. The solvent may be any liquid that wets the surfaces ofthe supporting structure and solubilizes the precursor.

A solvent which allows spontaneous wetting of the precursor solution onall available surfaces of a hydrophobic supporting structure ispreferred. The term "all available surfaces" includes withoutlimitation, the reticulated pores and interstices of a poroushydrophobic article or the tentacular surface of a film, bead or web.Spontaneous wetting provides rapid, even envelopment of all of theavailable internal and external surfaces of the article, and anapplication of at least an average of 10 monolayers thickness of theprecursor on such surfaces for further processing. It is possible for aporous supporting structure to have some pores having radii smaller thanthe hydrodynamic radius of the precursor. The surfaces along suchsmaller pores may not be available for application of the precursor,because the precursor molecule is too big to enter the pore.

The concentration of the precursor in solution determines the ability ofthe precursor to cover all available surfaces of the supportingstructure while substantially retaining the complex geometricconfiguration of the supporting structure. The concentration of theprecursor in the solvent may range from about 0.5 percent (w/v) to about15 percent (w/v). Desirably, the concentration ranges from about 2percent (w/v) to about 10 percent (w/v). Preferably, the concentrationranges from about 3 percent (w/v) to about 8 percent (w/v).

The solvent is desirably organic and has a significant vapor pressure ata temperature of less than about 38° C.

When the supporting structure is hydrophobic, the solvent may be anyliquid which solubilizes the precursor and wets the supportingstructures' surfaces. Non-limiting examples include: ketones, esters,ethers, nitriles, or amides having aliphatic, alicyclic, or aromaticgroups. Of these solvents, acetone, ethyl acetate, cyclohexanone,tetrahydrofuran, pyridine, acetophenone, and acetonitrile are desired.Of these solvents, acetone is preferred due to its availability, cost,and handling.

Hydrolysis Reagent

The hydrophobic polymeric poly(vinyl alcohol) precursor applied to thesurfaces of the supporting structure is convened, in-situ, to tacticpoly(vinyl alcohol) by a hydrolysis reagent which is capable ofconvening the pendant trifluoroacetate groups of the precursor intohydroxyl groups. The hydrolysis reagent may be applied in either aliquid or a gaseous state. The hydrolysis reagent may be acidic orbasic, but desirably it is basic. Thus, a desirable hydrolysis reagenthas a pH of greater than about 7.0 and desirably from about 8 to about10.

Non-limiting examples of a hydrolysis reagent include sodium hydroxidein methanol, sodium carbonate in a methanol/water solution, ammoniumhydroxide in methanol, potassium hydroxide in a methanol/water mixture,and aqueous or vaporous ammonia. Of these reagents, ammonia is preferredin the vapor phase or in a methanol/water mixture.

When vaporous ammonia is used, it is presently preferred to hydrate thesurfaces of the supporting structure and the shell of tactic poly(vinylalcohol) with water or moisture vapor to stabilize hydrophilicity of theshell. Otherwise, it is possible for the extremely thin shell ofpoly(vinyl alcohol) to conformationally rearrange, causing loss of someor a substantial portion of hydrophilicity, if such article is notplaced into use in aqueous-based solvents within weeks after manufactureof the hydrophilic article.

The amount of contact between the hydrolysis reagent and the precursorshould be sufficient in duration and in concentration to permit completeconversion of the tactic precursor to tactic poly(vinyl alcohol).Desirably, the polymeric supporting structure having the precursorapplied to its surfaces is immersed in a solution containing thehydrolysis reagent having a pH of greater than 7.0.

Method To Make The Article

The manufacture of an article having a hydrophilic polymeric shellvaries according to its composition and its ultimate shape.

The supporting structure may be formed from commercially availablematerials depending on form and composition desired by those skilled inthe art.

Raw materials suitable as base materials for supporting structures arecommercially available. For example, polymeric supporting structures maybe prepared from commercially available resins using a variety ofextrusion, membrane preparation, or film-forming techniques well knownin the art. A preferred method of membrane preparation is disclosed inU.S. Pat. No. 4,539,256, the disclosure of which is incorporated byreference herein.

Membranes of polysulfone are commercially available from Schleider andSchuell of Keene, N.H. Polyolefinic microporous membranes arecommercially available from Hoeschst-Celanese of Charlotte, N.C. andreferences to the methods of manufacture of such polyolefinicmicroporous membranes may be found in U.S. Pat. Nos. 4,501,793 and3,853,601, both of which are incorporated by reference herein.

For the poly(vinyl alcohol) precursor, a poly(vinyl trifluoroacetate)homopolymer may be made according to U.S. Pat. No. 2,436,144,incorporated by reference herein. A poly(vinyl trifluoroacetate)copolymer may be made according to U.S. Pat. No. 2,436,144 or accordingto co-assigned U.S. Pat. Nos. 4,528,325, and 4,618,649, both of whichare incorporated by reference herein.

Vinyltrifluoroacetate and comonomers for synthesis ofpoly(vinyltrifluoroacetate) are commercially available from Polysciencesof Warrington, Pa. and Aldrich Chemical of Milwaukee, Wis.

A solution of tactic, poly(vinyl alcohol) precursor in a solvent whichwets the supporting structure is then applied onto all availablesurfaces of the supporting structure, saturating the complex surfaces.Upon evaporation of the solvent, a self-interlocking shell is formedwhich substantially retains the complex geometric configuration of thestructure.

Depending upon the configuration of the supporting structure and itscomposition, the method of application of precursor solution may involvewiping, dipping, rolling, knifing or extruding steps as the casepermits. The solvent may be removed by drying the polymeric shell forsuch times and at such temperatures and pressures to fully dry theprecursor. Processing conditions may be controlled as necessary topermit drying of the precursor on surfaces without covering or cloggingavailable porous surfaces of the supporting structure. The applicationof precursor may occur batch-wise or continuously according to themanufacturing processing conditions preferred.

For example, to prepare an unclogged porous membrane, the in-situconversion of tactic precursor to tactic, hydrophilic poly(vinylalcohol) occurs by hydrolysis at less than about 38° C. using ahydrolysis reagent in either liquid or vaporous phase. A closed reactionvessel for vaporous reaction is preferred. A dipping tank for liquidreaction is preferred.

When ammonia vapor is used, after a closed vessel is employed, themembrane is dipped or sprayed with water or moisture vapor to lock inhydrophilicity of the poly(vinyl alcohol) shell.

While it is preferable to provide hydrophilic surfaces for thesupporting structure, it can be desirable in certain articles to be ableto reverse hydrophilicity into hydrophobicity after a process step orother intermediate activity. Hydrophilic shells of poly(vinyl alcohol)of the present invention can be conformationally rearranged intohydrophobic surfaces by heating the hydrophilic supporting structureabove the glass transition temperature (Tg) of poly(vinyl alcohol),about 80 degrees C., for a limited period of time. Without being limitedto a particular theory, it is believed that the increased mobility ofpoly(vinyl alcohol), above its Tg, allows a conformational rearrangementof hydroxyl groups at outer surfaces of the shell to point in towardsthe bulk of the shell. The driving force for this rearrangement is anatural desire to minimize interfacial energy (i.e., between the shellsurface and air). This results in the outermost few Angstroms of theshell surface being defined by the hydrocarbon backbone of thepoly(vinyl alcohol). Since "wetting" and hydrophilicity is defined bythe outermost few Angstroms of a surface, the presence of thehydrocarbon backbone in place of hydroxyl groups results in the surfaceno longer being hydrophilic. Thus, the shell has the same chemistry butis hydrophobic.

Hydrophobic poly(vinyl alcohol) can be converted to hydrophilicpoly(vinyl alcohol) by wetting surfaces of the shell-covered supportingstructure with a polar, water-miscible solvent, such as methanol oracetone, followed by solvent exchanging water into pores of thesupporting structure and drying. In such re-hydrophilization, contact ofa poly(vinyl alcohol) shell with such polar, water miscible solventre-orients hydroxyl groups out from such surfaces. Water or moisturevapor plasticizes poly(vinyl alcohol), swells such shell, and lowers theglass transition temperature thereof in the presence of such a polarenvironment.

Thus, according to methods of the present invention, one can controlhydrophilization of supporting structures, throughout all surfaces, onlyat outer surfaces, or only in pores or interstices. One can createregio-specific hydrophilic surfaces for a supporting structure accordingto need. Non-limiting examples of such regio-specific surfaces can bepatterned hydrophilicity throughout specific portions of a porousmembrane, "facade" hydrophilicity of a porous membrane, or a "sandwich"hydrophilicity having hydrophobic inner pores and interstices.

Alternatively, regio-specific hydrophilization can be achieved byintroducing a hydrolysis reagent only to designated portions of surfacesof a supporting structure covered with polymeric poly(vinyl alcohol)precursor. Also, such regio-specific hydrophilization can be achieved byapplying polymeric poly(vinyl alcohol) precursor to designated portionsof surfaces of the supporting structure, followed by hydrolysis of suchportions with hydrolysis reagent.

However, some uses of the article may prefer skinned, covered or cloggedpores, to convert a fractal geometric configuration of the article to aEuclidean geometric configuration. In such circumstances, processingconditions or solutions may be adjusted as desired. Three parameters maybe adjusted. Choice of solvent influences rate of coverage andevaporation. Precursor concentration determines solution viscosity, rateof pore penetration, and shell thickness. Pore sizes of surfaces of thearticle also determine rate of pore penetration.

FIG. 1 illustrates the comparison between a hydrophobic microporousmembrane (prepared according to Example 23 of U.S. Pat. No. 4,539,256)and a microporous membrane having with tactic, hydrophilic poly(vinylalcohol) shell (prepared according to the present invention). The outersurfaces of the article in scanning electron photomicrograph 1a arehydrophobic and untreated. The outer surfaces shown in scanning electronphotomicrograph 1b are hydrophilic due to the tactic, hydrophilicpoly(vinyl alcohol) shell about its surfaces. The treated membrane shownin scanning electron photomicrograph 1b retains its fractal geometricconfiguration because its complex surfaces are substantially as open andunclogged as the unprocessed membrane in photomicrograph 1a. Thus, thepores and interstices of supporting structure are not filled or occludedby the in-situ generated poly(vinyl alcohol) shell. The fractalconfiguration of the supporting structure is not converted to aEuclidean configuration. Thus, the membrane retains its structuraladvantages while adding hydrophilic surfaces.

FIG. 2 illustrates that a microporous membrane having a tactic,hydrophilic poly(vinyl alcohol) shell enveloping both outer and innerporous surfaces of the membrane does not clog or occlude any pores orinterstices. Scanning electron photomicrograph 2a of the samehydrophobic membrane as in FIG. 1a and scanning electron photomicrograph2b of the same hydrophilic membrane as in FIG. 1b both show about 10microns of cross-section of the membrane at the bottom of the scanningelectron photomicrographs, with the remainder being a perspective viewof the outer surface. No significant difference can be seen betweenthese two photos.

While not being limited to any particular theory, it is believed thatthe shell of tactic poly(vinyl alcohol) envelops available surfaces ofthe supporting structure by forming tie molecules among crystallitemolecules. FIG. 3a illustrates a membrane microstructure which isenveloped by a poly(vinyl alcohol) shell. The exploded view of FIG. 3bprovides another illustration of the enveloped polymeric structure. Tiemolecules of poly(vinyl alcohol), such as those described in Basset,D.C., Principles of Polymer Morphology, Cambridge Univ. Press, 1981,between crystallites of poly(vinyl alcohol), provide theself-interlocking strength of the shell. The complex geometricconfiguration of the underlying polymeric structure is substantiallyretained after envelopment of from about an average of 10 to about anaverage of 4000 monolayers of poly(vinyl alcohol) and desirably fromabout an average of 10 to about an average of 400 monolayers ofpoly(vinyl alcohol).

Usefulness Of The Invention

The hydrophilic supporting structures of the present invention can beutilized in several applications involving aqueous fluids or hydrophilicorganic solvents. The chemical inertness and complex geometricconfiguration of many hydrophobic materials or structurally weakhydrophilic materials would make them ideally suited for hydrophilicprocesses if the supporting structure had hydrophilic surfaces of aself-interlocking shell.

Having a tactic, hydrophilic poly(vinyl alcohol) shell envelopingsurfaces of such hydrophobic supporting structures enables suchstructures to be used in aqueous systems or in hydrophilic organicsolvents in which the untreated supporting structure above would beinadequate, incompatible, or ineffective, notwithstanding its complexgeometric configuration desired for such mechanical processes. Therelative insolubility of the tactic, hydrophilic poly(vinyl alcohol)shell in a large number of organic solvents and water enables thearticle to be used in those circumstances where the solvent must wet thearticle in order for the article to perform its intended purpose. Auseful measure of "wetting" capability is pore wetting surface energy.

"Pore wetting surface energy" means the surface energy of the supportingstructure required for spontaneous wetting of a pore through the wickingof water into the pore via capillary forces. Spontaneous wetting of thepore occurs when the surface energy of the internal surface of the poresis high enough for water to have less than a 90° contact angle with thesurface. Analytically, according to Wu, S., Polymer Interface andAdhesion, Marcel Dekker, New York, 1982, p. 244, spontaneous wettingoccurs when the capillary force, ΔP_(c), in the following equation ispositive:

    ΔP.sub.c =2σ.sub.L cosΘ/r

where σ_(L) is liquid surface tension (72.8 dynes/cm for water), Θ isthe contact angle (<90°), and r is the pore radius.

The magnitude of the positive capillary force correlates to the rate ofspontaneous wetting. The variation in pore size and complex geometricconfiguration also assists in controlling the rate of migration.

The tactic, hydrophilic poly(vinyl alcohol) shell enveloping thesupporting structure also provides the advantage of increasing themechanical strength of a supporting structure. By enveloping internaland external surfaces of a membrane while substantially retaining thecomplex geometric configuration of the membrane (e.g., a microporousmembrane having pore sizes of from about 0.01 μm to about 1.2 μm,) thetactic poly(vinyl alcohol) shell increases the tensile strength andpercent elongation properties of the supporting structure. While notlimited by any particular theory, it is believed that the enhancedtensile strength is achieved by the covering of acute geometricinterstices of the fibrillar structure which would otherwise be probablestress concentration points for failure initiation in the complexgeometric configuration. While acute geometric intensities may belessened, the overall complex geometric configuration is substantiallyretained.

The presence of a tactic, hydrophilic poly(vinyl alcohol) shell about asupporting structure provides highly reactive hydroxyl sites for furtherchemical, physical, and biological uses.

The present invention has broad utility in that articles having durablehydrophilic polymeric shells can be prepared from a wide variety ofsupporting structure materials which can comprise any of severalcompositions and take any of several forms. The present invention'sability to provide articles having a non-crosslinked self-interlockingshell comprising hydroxyl functionality that displays minimal solubilityin water and aqueously soluble organic solvents provides advantages notpreviously found in the art.

Drug Delivery Devices

Microporous polyolefinic membranes could have considerable usage forcontrolled delivery of hydrophilic therapeutic agents if the microporousmembrane were hydrophilic. The tactic, hydrophilic poly(vinyl alcohol)shell on all available surfaces of a microporous polyolefinic membranerenders the surfaces hydrophilic without substantially altering thecomplex geometric configuration of the membrane.

A drug delivery device using a hydrophilic microporous membrane as acomponent thereof may take several forms, such as that shown in FIGS.4-6.

In FIG. 4, the drug delivery device 10 is shown. The device 10, usefulfor either topical or transdermal drug delivery, comprises a backinglayer 12 sealed to a membrane 14 which forms a reservoir 16 for thetherapeutic agent 17. A hypoallergenic pressure-sensitive adhesive layer18 is coated on the membrane 14 and protected by a release liner 19.

The therapeutic agent 17 is typically hydrophilic or can benefit fromthe hydrophilic surface. A hydrophilic shell of tactic poly(vinylalcohol) on a microporous membrane 14 having pore sizes of from about0.5 μm to about 0.8 μm facilitates the migration of the therapeuticagent 17 through the membrane 14 and into adhesive 18 for delivery tothe skin of a patient after release liner 19 is removed. By variation ofthe pore size of membrane 14, the rate of migration of therapeutic agent17 to the skin may be controlled, so long as the rate of migrationthrough the pressure sensitive adhesive 18 is at least as fast as therate of migration through membrane 14.

FIG. 5 illustrates another embodiment of a drug delivery device 20. Thedevice 20 has a backing 22 and a membrane 24 sealed to provide areservoir 26 within which therapeutic agent 27 is stored. Hypoallergenicpressure-sensitive adhesive layer 28 extends about the perimeter of thedevice 20. A release liner 29 protects the pressure-sensitive layer andthe membrane 24 until use is desired. An example of this construction isdisclosed in U.S. Pat. No. 4,855,294.

The difference between the embodiment shown in FIG. 5 and the embodimentshown in FIG. 4 is the absence of the pressure-sensitive adhesive layerin the pathway of the therapeutic agent 27 from reservoir 26 to the skinof the patient. Thus, therapeutic agent 27 need only migrate throughporous membrane 24 in order to contact the skin of the patient. The rateof migration may be controlled by selection of the microporous membrane24 having different thicknesses and pore sizes without being limited bythe rate of migration of the therapeutic agent 27 throughpressure-sensitive adhesive 28.

FIG. 6 illustrates yet another embodiment of the use of a hydrophilicmicroporous membrane of the present invention in drug delivery device30. In this instance, backing material 32 is sealed to membrane 34without providing a reservoir. Rather, therapeutic agent 37 is storedwithin membrane 34 as a depot for subsequent delivery throughpressure-sensitive layer 38 to the skin of the patient after releaseliner 39 is removed. The microporous complex geometric configuration ofthe membrane 34, the thickness of the membrane 34 and the celldimensions of the pores may be adjusted to accommodate certainconcentrations or volumes of therapeutic agent 37 as desired for topicalor transdermal delivery to or to and through the skin of the patient,respectively.

Rarely is therapeutic agent 17, 27 or 37 used alone in the drug deliverydevice. Excipients are often also present as solvents or penetrationenhancing agents. Solvents assist the placement of the therapeutic agentin the device. Penetration enhancing agents assist the penetration ofthe therapeutic agent to and through the skin. These excipients alsomigrate through the membrane 14, 24 or 34 with the therapeutic agent 17,27, or 37. The hydrophilicity of the membrane 14, 24 or 34 imparted bythe tactic poly(vinyl alcohol) shell may also aid in excipientmigration.

The membrane 14, 24 or 34 is desirably made from polyolefinic polymericstructures which can be heat sealed to the backing 12, 22 or 32,respectively, using heat sealing techniques known to those skilled inthe art, e.g. pressing between heated platens. The poly(vinyl alcohol)shell on the surfaces of membrane 14, 24, or 34 does not prevent theheat sealing of the membrane to the backing.

The backing 12, 22 or 32 can be any backing material known to thoseskilled in the art and useful for drug delivery devices. Non-limitingexamples of such backing materials are polyethylene, ethylene-vinylacetate copolymer, polyethylene-aluminum-polyethylene composites, and"ScotchPak™" brand backings commercially available from Minnesota Miningand Manufacturing Company of St. Paul, Minn. (3M).

The hypoallergenic pressure-sensitive adhesive layer can be anyhypoallergenic pressure-sensitive adhesive composition which may becoated on the membrane of the present invention. Non-limiting examplesof pressure-sensitive adhesive compositions useful in drug deliverydevices are acrylate-based pressure-sensitive adhesives disclosed inU.S. Pat. No. 4,737,559, the disclosure of is incorporated herein byreference.

The release liner 19, 29 and 39 may be any release liner material knownto those skilled in the art. Non-limiting examples of such releaseliners commercially available include siliconized polyethyleneterephthalate films commercially available from H. P. Smith Co. andfluoropolymer coated polyester films commercially available from 3Munder the brand "ScotchPak™" release liners.

The therapeutic agent may be any water soluble or otherwise hydrophilictherapeutically active material known to those skilled in the art andapproved for delivery to or through the skin of a patient. Non-limitingexamples of therapeutic agents useful in transdermal delivery devicesare peptides or short chain proteins, the salt form of any active drugused in transdermal applications and permeable to mammalian skin throughthe use of penetration enhancing agents, or growth factors for use inenhancing wound healing. Other therapeutic agents are identified asdrugs or pharmacologically active agents and are disclosed in U.S. Pat.Nos. 4,849,224 and 4,855,294, and PCT Patent Publication WO 89/07951.

Excipients or penetration enhancing agents are also known to thoseskilled in the art. Non-limiting examples of penetration enhancingagents include ethanol, methyl laureate, oleic acid, isopropylmyristate, and glycerol monolaurate. Other penetration enhancing agentsknown to those skilled in the art are disclosed in U.S. Pat. Nos.4,849,224; and 4,855,294 and PCT Patent Publication WO 89/07951.

The method of manufacturing a transdermal delivery device depends on itsconstruction.

The drug delivery device 10 shown in FIG. 4 may be constructed using thefollowing general method. A solution or a slurry is prepared byhomogeneously mixing a therapeutic agent 17, other constituents of thereservoir (e.g., gelling agents, skin penetration enhancing agents,diluents, and other excipients), and a suitable solvent. The solution orslurry is placed into a dispenser on form fill and seal equipment. Alaminate of microporous membrane 14, adhesive layer 18, and releaseliner 19 is constructed and passed underneath the dispenser. Apre-measured quantity of the solution or slurry is deposited from thedispenser on the laminate. Backing layer 12 is then applied over thequantity of solution or slurry. The backing layer 12 is heat-sealed tothe membrane 14 around the quantity of solution or slurry, creating areservoir 16. The resulting laminate of backing 12, reservoir 16,membrane 14, adhesive 18, and liner 19 is usually made in large sheetsfrom which individual devices 10 of the desired shape and size may becut.

The drug delivery device 20 shown in FIG. 5 may be made in the samemanner as described in FIG. 4, except that the location(s) of theadhesive layer 28 is different. The adhesive layer 28 is pattern-coatedon release liner 29 and laminated to membrane 24. The pattern-coating isarranged so that when the laminate of membrane 24, layer 28 and liner 29is finally assembled, there is no adhesive layer 28 between thelocation(s) of reservoir 26 and the liner 29.

The drug delivery device 30 shown in FIG. 6 may be prepared using thefollowing general method. A solution is prepared by dissolving thetherapeutic agent 37 and such optional excipients as are desired in asuitable solvent. The membrane 34 of the present invention is immersedin or coated with the solution containing the therapeutic agent 37 toeffect diffusion of the therapeutic agent and any excipient into theporous structure of the membrane 34. The resulting loaded membrane 34 islaminated to the backing layer 32. A solution, or optionally anemulsion, of the adhesive is coated onto the release liner 39 andallowed to dry to form adhesive layer 38. The exposed face of themembrane 34 is laminated to the exposed face of the adhesive layer 38 tocomplete the assembly. Again, the resulting laminate is usually made inlarge sheets from which individual devices 30 of the desired shape andsize may be cut.

The usefulness of the hydrophilic microporous membranes of the presentinvention are not limited to drug delivery devices which are placed onthe skin of a patient. Non-limiting examples of other uses include (a)construction of a device with two hydrophilic microporous membranes heatsealed together to form a reservoir pocket for drug delivery in multipledirections, such as for subdural or intra-muscular drug delivery; and(b) construction of a hydrated membrane to be used in conjunction withiontophoresis to provide a salt bridge to electrically diffuse chargedactive agents across the hydrophilic porous membrane and to the skin.

This invention is not limited to the embodiments described here or bythe examples which follow.

EXAMPLES

In the examples to follow, certain tests were conducted and aredescribed below:

Gurley Value--This value is a measurement of time in seconds to pass 50cm³ of air through a porous film according to ASTM D-726, Method A.

Bubble Point Pore Size--This is a measurement of the maximum effectivepore size, in microns, according to ASTM F-316. This value is alsoreferred to as "pore size" in the Examples.

Porosity--This is a measure of the void volume of the porous article,and is derived from the measurement of specific gravity of the article,according to ASTM D-792.

The porosity is defined as: ##EQU1##

Tensile Strength--Values measured according to ASTM D 638-80 using anInstron model 1122 tensile tester under the following conditions:

Jaw Gap: 5.08 cm

Jaw Speed: 50.8 cm/min

Sample Size: 2.54 cm wide strip

MD and TD values for the tensile strength refer to measurements made inthe "machine direction" and the "transverse direction" respectively.

Water Permeability--Water permeability was determined by placing a 74 mmdiameter piece of the membrane in a test cell, which used an o-ring toseal the membrane to a sintered stainless steel back-up plate. The cellwas equipped with a 350 ml water reservoir and was pressured withcompressed nitrogen. The water flow rate was calculated by measuring thevolume of water passed through the sample in a given time, with a 10 psi(or 68,947 N/m²) head pressure. At least three measurements wereaveraged for each permeability value reported.

Example 1

Preparation of the poly(vinyl alcohol) precursor, syndiotacticpoly(vinyl trifluoroacetate), was performed in a one gallon glass bowljacketed pressure reactor having a stainless steel lid fitted with ametal turbine agitator blade on a sealed shaft, two mixing vanes, athermowell and at least two valved openings. The system was purged witha sweep of dried argon to remove moisture and oxygen before addingreactants or solvent. Materials were weighed and transferred in closedvessels under inert gas and anhydrous conditions. Charges were madethrough rubber septa covering the opened valves in the reactor lid usingproper techniques to prevent uptake of atmospheric moisture and oxygen.Into the reactor were placed, in order, 3025 g of Freon 113, 17.5 ml ofa premix containing 2.5 g of trifluoroacetic anhydride in 25 ml of Freon113, 355 g vinyl trifluoroacetate monomer, 14 ml of a second premixcontaining 2.5 g of bis(4-t-butylcyclohexyl) peroxydicarbonate(commercially available as "Percadox" 16N from Akzo Chemie America,Noury Chemicals of Chicago, Ill.) in 25 ml of Freon 113. The reactortemperature was raised to 45° C. and maintained at that temperature forabout 18 hours with an agitator speed at about 1000 rpm. A slightexotherm was observed during the reaction with a maximum system pressureof about 10-12 psig (0.7-0.8 kg/cm²). The polymerized, syndiotacticpoly(vinyl trifluoroacetate) (PVTFA) was isolated by filtration anddried at 40° C. under vacuum overnight.

A microporous polyethylene (PE) membrane, made by thermally inducedphase separation as disclosed in Example 23 of U.S. Pat. No. 4,539,256(Shipman) the disclosure of which is incorporated herein by reference,having a maximum pore size of 0.5 micron, a porosity of 81.5 percent anda thickness of 0.074 mm, was saturation treated with a 4 percent (w/v)acetone solution of PVTFA using an extrusion die. The membrane was driedslowly for 1.6 minutes in a two zone air floatation oven with the twozones set at temperatures of 27° C. and 38° C. respectively, resultingin a 22.2 weight percent add on of the PVTFA shell formed on theexternal and internal pore surfaces. No substantial blocking of thepores occurred, nor was a PVTFA skin formed on the covered side asevidenced from scanning electron microscopy (SEM) analysis. The complexgeometric configuration of the membrane was substantially retained.Bubble point measurements showed a reduction in the maximum pore size to0.44 micron.

A piece of this dry membrane was placed in an ammonia-saturated glassvessel for 2 minutes in order to convert, in-situ, the PVTFA shell to apoly(vinyl alcohol) (PVA) shell. The ammonia atmosphere was generated byplacing a concentrated ammonium hydroxide solution in the bottom of thevessel. A 68 weight percent reduction in the weight of the shellresulted from the hydrolysis reaction.

Fourier Transform Infrared, (FT-IR), spectroscopy (at 4 cm⁻¹ resolution,64 scans, between a range of 4000 cm⁻¹ and 400 cm⁻¹, through themembrane) confirmed that the 68 weight percent loss in shell weight,which occurred during this basic hydrolysis reaction step was due to thequantitative loss of the trifluoroacetate group from the PVTFA. Thisamount of weight loss corresponded exactly to the amount of weight lossexpected for 100% conversion from PVTFA to PVA. Upon removing themembrane from the ammonia atmosphere, it displayed spontaneous andnearly instantaneous wetting with water. The complex geometricconfiguration of the membrane was substantially retained throughout thehydrolysis treatment as was evidenced by a pore size loss of less thaneight percent.

The ability of the hydrophilic membrane to resist wash-out of the PVAshell by common organic solvents was demonstrated by soaking pieces ofthe membrane in large amounts of acetone, isopropyl alcohol, and1,1,1-trichloroethane. After 45 minutes of soaking in each of thesesolvents, the re-dried membranes retained their hydrophilicity, as shownby their spontaneous and nearly instantaneous wetting with water. Theability of the hydrophilic membrane to resist wash-out of the PVA shellby water was demonstrated by passing 2000 ml of deionized water througha 36 cm² piece of this membrane. After drying, the hydrophilicity of themembrane remained unchanged (i.e., it was spontaneously and nearlyinstantly wetted with water).

The porous properties of the starting PE microporous membrane, the PVTFAcovered membrane, and the final PVA shell hydrophilic membrane arereported in Table 1 below.

                                      TABLE 1                                     __________________________________________________________________________               Coating          Percent Pore     Water                            Membrane   Weight                                                                             Thickness                                                                           Pore Size                                                                           Size Loss                                                                            Porosity                                                                           Gurley                                                                             Permeability*                    __________________________________________________________________________    PE         --   0.074 mm                                                                            0.496μ                                                                           --     81.5%                                                                               9.4 sec                                                                           0**                              PVTFA covered PE                                                                         22.2%                                                                              0.056 mm                                                                            0.438μ                                                                           12%    73.2%                                                                              17.6 sec                                                                           0**                              PVA shelled PE                                                                            8.4%                                                                              0.056 mm                                                                            0.436μ                                                                            7%    73.6%                                                                              15.2 sec                                                                           0.052                                                                         L/(m.sup.2 *hr*Pascals)          __________________________________________________________________________     *Water permeability measured at 68,930 Pascals (10 psi).                      **No flow of water occurs at 68.930 Pascals through this hydrophobic          membrane without an ethanol prewetting step due to the hydrophobicity of      PE and PVTFA. When measured after ethanol prewetting and a solvent            exchange of water, PE Water Permeability measured 0.043 and PVFTA coated      PE Water Permeability measured 0.033 L/m.sup.2 *hr*Pascal), respectively.

Example 2

A hydrophilic membrane was prepared according to the procedure ofExample 1 except that the syndiotactic PVTFA solution was applied to themembrane using a #8 wire-wound bar to spread the PVTFA solution on themembrane. The sample was allowed to dry at room temperature in aventilation hood to produce a PVTFA treated membrane without causingpore blockage or PVTFA skin formation as shown by SEM examination. ThePVTFA treated membrane retained the complex geometric configuration ofthe starting membrane. The sample was reacted with vaporous ammonia asin Example 1 to yield a hydrophilic membrane, as shown by itsspontaneous and nearly instantaneous wetting with water.

Example 3

Table 2 below provides data on mechanical properties of unprocessedhydrophobic microporous membranes and the hydrophilic microporousmembranes of the present invention, both before and after in-situconversion to the corresponding PVA shell membrane. The base PE membranewas the same as that used in Example 1. The PVTFA treated membranes wereprepared according to the procedure detailed in Example 2, using variousconcentrations of syndiotactic PVTFA solutions in acetone as noted inTable 2 below. Hydrolysis of the PVTFA treated membranes was performedin an ammonia atmosphere as in Example 1. The PVTFA add-on wasdetermined by weight difference after a piece of the PVTFA treatedmembrane had been extracted with acetone to a constant weight. Theweight percent of PVA was calculated from the weight percent PVTFAabove, assuming 100 percent conversion to PVA. Tensile measurements wereperformed on 2.54 cm wide strips of membrane as described above. Tensilestrength is defined as the Newtons/m² at break normalized to thecross-sectional area.

                                      TABLE 2                                     __________________________________________________________________________                                    Tensile Strength                                                     Weight Percent                                                                         At Break   Elongation                         Membrane Description   PVTFA    ((Newtons/m.sup.2) × 10.sup.6                                                      To Break (%)                       Example                                                                            Solution Concentration                                                                          or PVA Add On                                                                          MD   TD    MD  TD                             __________________________________________________________________________    3A   Uncoated PE from Ex. 1                                                                          --       5.76 0.32  47  107                            3B   Ex. "3A" covered with 4% PVTFA                                                                  29.2     9.33 5.79  38  53                             3C   Ex. "3B" after conversion to PVA                                                                9.3      10.13                                                                              6.64  66  118                            3D   Ex. "3A" covered with 6% PVTFA                                                                  36.1     9.82 6.40  28  46                             3E   Ex. "3D" after conversion to PVA                                                                11.6     10.43                                                                              7.34  43  97                             3F   Ex. "3A" covered with 8% PVTFA                                                                  42.0     9.88 6.55  20  45                             3G   Ex. "3F" after conversion to PVA                                                                13.4     11.62                                                                              7.97  50  91                             __________________________________________________________________________

Example 4

A microporous PE membrane, prepared according to Example 23 of U.S. Pat.No. 4,539,256 (Shipman), having 0.26 micron pore size and a 77 percentporosity was treated with a 4 percent (w/v) solution of syndiotacticPVTFA (prepared according to Example 1) in cyclohexanone. The web waspassed through an immersion trough containing the tactic PVTFA solution,which was heated to 46° C. to decrease its viscosity, then passedthrough a rubber nip station to squeeze off excess solution, and driedin an air floatation oven at a temperature of 40.5° C. to produce aPVTFA treated membrane. Control of the PVTFA add-on was more difficultusing this method, and the membrane had a tendency to stretch as itpassed through the nip roll station. After hydrolysis with ammoniavapor, as in Example 1, the membrane was hydrophilic as shown by itsspontaneous and nearly instantaneous wetting with water.

Example 5

A microporous polypropylene (PP) membrane, made according to theprocedure of Example 9 of U.S. Pat. No. 4,726,989 (Mrozinski), thedisclosure of which is incorporated herein by reference, was treatedwith a 4 percent (w/v) acetone solution of syndiotactic PVTFA followingthe procedure of Example 2. Upon hydrolysis with ammonia vapor as inExample 2, the membrane was hydrophilic, as demonstrated by itsspontaneous and nearly instantaneous wetting with water. The porousproperties of the starting PP membrane and the hydrophilic membrane ofthe present invention are shown in Table 3. Pore size loss was less than11 percent, demonstrating a substantial retention of the physicalstructure of the membrane while imparting hydrophilicity to the membranesurfaces.

                                      TABLE 3                                     __________________________________________________________________________             Weight            Percent                                                     Percent PVA       Pore Size     Water                                Sample   Add-On Thickness                                                                           Pore Size                                                                          Loss Porosity                                                                           Gurley                                                                            Permeability*                        __________________________________________________________________________    PP       --     0.081 mm                                                                            0.974μ                                                                          --   82.9%                                                                              3.3 sec                                                                           0**                                  PVA shelled PP                                                                         10.2%  0.076 mm                                                                            0.874μ                                                                          11%  79.2%                                                                              3.7 sec                                                                           0.15                                                                          L/(m.sup.2 *hr*Pascals)              __________________________________________________________________________     *Water permeability measured at 68,930 Pascals.                               **No flow of water occurs at 68,930 Pascals through this hydrophobic          membrane without an ethanol prewetting step due to the hydrophobicity of      PP. When measured after ethanol prewetting and a solvent exchange of          water, PP water permeability measured 0.13 L/(m.sup.2 *hr*Pascals).      

Example 6

A 0.023 mm thick PP microporous membrane, prepared according to Example9 of U.S. Pat. No. 4,726,989, having a 0.2 micron pore size, a 66.7percent porosity, and a Gurley value of 25.6 sec, was treated with PVTFAaccording to the procedure of Example 2, using a 2 percent (w/v)solution of syndiotactic PVTFA in acetone followed by in-situ NH₃hydrolysis. The treatment/hydrolysis operation was repeated three timesto prepare the hydrophilic membrane of the present invention. Theresulting hydrophilic membrane was instantaneously wet with water. Theability of the PVA shell to resist wash-out by water was demonstrated byplacing the membrane in boiling water for 5 hours, drying the membrane,and demonstrating that the membrane was still spontaneously and nearlyinstantaneously wet with water, even though there was a 1.8 percentreduction in the membrane's weight during the exposure to boiling water.

Example 7

The syndiotactic PVTFA treated membrane of Example 1 was placed in astream of anhydrous NH₃ for 2 seconds. The NH3 stream was directedagainst the membrane so as to force the ammonia through the pores of themembrane. After this dry ammonolysis treatment, the hydrophilicity ofthe membrane was comparable to the hydrophilicity of the membrane ofExample 1, as shown by spontaneous and nearly instantaneous wetting withwater. FT-IR showed that 100 percent conversion of the PVTFA to PVA wasaccomplished. This demonstrated that the 2 minute ammonolysis time ofExample 1 was only required in order to allow the NH₃ vapor to diffuseinto the pores, and that by forcing the NH₃ into the pores, the trueease of conversion to PVA is appreciated.

Example 8

The ability to convert syndiotactic PVTFA treated membranes into PVAshell membranes using a variety of hydrolysis reagents and conditionswas demonstrated by dipping the PVTFA treated membrane of Example 1 intosolutions of various bases as well as a HCl solution. The results areshown in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Example Hydrolysis        pH Immersion Time                                                                         Result                                  __________________________________________________________________________    Comparison 8A                                                                         0.5M HCl in MeOH  <2 30 min   not hydrophilic                         8B      0.1M NaOH in MeOH 13 30 min   hydrophilic                             8C      0.1M Na.sub.2 CO.sub.3 IN 50:50.MeOH:H.sub.2 O                                                  -- 30 min   hydrophilic                             8D      10% conc. NH.sub.4 OH in MeOH                                                                    8 30 min   hydrophilic                             8E      0.1M KOH in H.sub.2 O                                                                           13 30 min   outside surface                                                               hydrophilic                             8F      0.1M KOH in H.sub.2 O                                                                           13 4 days   outside surface                                                               hydrophilic                             __________________________________________________________________________

In order to effect the conversion of PVTFA to PVA throughout themembrane, the solution must be able to wet the PVTFA treated membrane,or the base must be volatile in order to deliver the hydrolysis reagentto the internal pore surfaces (c.f. Examples 10E and 10F). The 30 minuteimmersion time was probably excessive, but was chosen to ensure completehydrolysis. All cases that resulted in a hydrophilic membrane (Examples10B, 10C and 10D) showed 100 percent conversion of the PVTFA to PVAunder FT-IR analysis performed according to Example 1.

Example 9

The PE microporous base membrane of Example 1 was treated, as in Example2, with 4 percent (w/v) syndiotactic PVTFA solutions in various solventsas noted in the Table 5 below. This example demonstrates that a varietyof solvents other than the preferred acetone, including: esters, cyclicethers, aliphatic and aromatic ketones, nitriles, and amides, can beused to prepare PVTFA treated membranes. Also, shown by comparison, aresolvents which could not be made to work, due to the substantialinsolubility of PVTFA in these solvents. Copolymers of PVTFA, describedin other examples within this disclosure, are not limited to thesolvents listed below.

                                      TABLE 5                                     __________________________________________________________________________    Example Solvent        Coating Conditions                                                                       Result                                      __________________________________________________________________________    9A      Ethyl Acetate  Room Temp. (21° C.)                                                               hydrophilic                                 9B      Tetrahydrofuran                                                                              40° C. on PE                                                                      hydrophilic                                 9C      Dimethyl Formamide                                                                           Room Temp. (21° C.)                                                               hydrophilic                                 9D      Acetophenone   80° C. on PP                                                                      hydrophilic                                 9E      Acetonitrile   Room Temp. (21° C.)                                                               hydrophilic                                 Comparison 9F                                                                         Diethyl Ether  --         PVTFA not substantially soluble             Comparison 9G                                                                         1,1,1-Trichloroethane                                                                        --         PVTFA not substantially soluble             Comparison 9H                                                                         Aliphatic Alcohols        PVTFA not substantially soluble                     (i-PA, EthOH, n-PA, n-BuOH)                                           Comparison 9I                                                                         Trifluoroacetic Acid                                                                         --         PVTFA not substantially soluble             Comparison 9J                                                                         1,1,1-Trifluoroethanol                                                                       --         PVTFA not substantially                     __________________________________________________________________________                                      soluble                                 

Example 10

Microporous PE membrane samples, prepared according to Example 23 ofU.S. Pat. No. 4,539,256, having a pore size of 0.548 μ, a thickness of0.056 mm, a porosity of 88 percent, and a Gurley value of 5.4 sec, weretreated, as in Example 2, with 4 percent (w/v) acetone solution ofsyndiotactic PVTFA copolymers having either vinyl acetate or maleicanhydride as the comonomer. The copolymers were prepared by free radicalpolymerization of the appropriate ratio of vinyl trifluoroacetate andthe corresponding vinyl comonomer (i.e., vinyl acetate or maleicanhydride, respectively) according to Examples 1 to 4, respectively, ofU.S. Pat. No. 4,618,649 (Ofstead), which is incorporated herein byreference. In-situ hydrolysis of these treated membranes produced PVAshell membranes which were hydrophilic as evidenced by spontaneous andnearly instantaneous wetting with water. In order to show that thecrystallinity of the hydrophilic PVA shell was not excessively disruptedby the incorporation of less than about 5 percent of comonomer, each PVAshell membrane sample was subjected to a water extraction to determinePVA loss. Initial PVTFA and PVA add-ons were determined according to theprocedures of Example 3. One liter of water was passed through a disc ofeach PVA shell membrane having a surface area of 36.3 cm² and theresulting PVA weight loss calculated by weight differential of themembrane sample. The weight loss results tabulated in Table 6 show thatless than 1 weight percent of the membrane weight was lost due to thewater wash step. The hydrophilicity of the washed and dried samples werecomparable to the hydrophilicity of the unwashed membranes,demonstrating that the presence of less than about 5% comonomer had notsignificantly disrupted the crystallinity of the PVA.

                  TABLE 6                                                         ______________________________________                                                                   %                                                                             Weight                                             Example Copolymer          Add-On    Loss*                                    ______________________________________                                        10A     PVTFA-co-MA (99.7/0.3)                                                                           12.2      -0.25                                    10B     PVTFA-co-MA (99.9/0.1)                                                                           8.5       -0.05                                    10C     PVTFA-co-MA (99.95/0.05)                                                                         10.1      -0.10                                    10D     PVTFA-co-VA (96.0/4.0)                                                                           9.5       0.85                                     10E     PVTFA-co-VA (98.5/1.5)                                                                           9.2       0.30                                     ______________________________________                                         *Negative weight loss indicates a net weight gain. Even though care was       taken to use prefiltered water for the flushing, some particulate matter      may have collected on the membrane, or these numbers may simply reflect       the inherent imprecision of the weight measurement. In any case there was     a negligible weight loss due to flushing these samples with water.       

Example 11

A microporous polysulfone membrane having a surfactant coating to renderit hydrophilic and having a rated 0.45 micron pore size (obtained fromSchleicher & Schuell) was rinsed in isopropyl alcohol to remove thesurfactant coating. The then hydrophobic polysulfone membrane wassaturation-treated with a 4 percent (w/v) solution of syndiotactic PVTFAin acetophenone (a poor solvent for polysulfone) following the procedureof Example 2. The resulting PVTFA treated membrane was hydrolyzed in anammonia atmosphere according to the procedure of Example 2 to produce ahydrophilic PVA shell membrane which was spontaneously and nearlyinstantaneously wet with water.

Example 12

A microporous polyvinylidene fluoride, PVDF, membrane made according toExample 22 of U.S. Pat. No. 4,539,256, having a 0.21 micron pore size, a72 sec Gurley value and a 58.3 percent porosity, was saturation-treatedwith a 4 percent (w/v) solution of syndiotactic PVTFA by forcing thesolution through the membrane by applying a partial vacuum to theopposite side of the membrane. The resulting PVTFA treated membrane washydrolyzed in an ammonia atmosphere according to the procedure ofExample 2 to produce a hydrophilic membrane that was spontaneously andnearly instantaneously wet with water.

Example 13

Polyethylene microporous membranes, prepared according to Example 23 ofU.S. Pat. No. 4,539,256, having a range of porosities and pore sizes,were treated with a 4 percent (w/v) solution of syndiotactic PVTFA inacetone according to the procedure of Example 1. Upon hydrolysis withthe ammonia vapor according to the procedure of Example 2, hydrophilicPVA shell membranes which were spontaneously and nearly instantaneouslywet with water were produced. The porosity, pore size and Gurley valuesof both the starting membranes, numbers 13A, 13C, 13E, and 13G, and thePVA shell membranes, numbers 13B, 13D, 13F, and 13H, are tabulated inTable 7, along with comments concerning the amount of surface poreblockage that occurred. The extensive pore blockage noted with the 0.101μm pore size membrane is due to the fact that the solution evaporatesmore rapidly than it can penetrate into the small pores which results inthe formation of a pore-blocking skin at the surface of the membrane.Solvents having lower vapor pressures and/or lower viscosity solutionsshould lessen the occurrence of this type of pore-blocking skinformation.

                  TABLE 7                                                         ______________________________________                                        Sample                                                                              Porosity Pore Size                                                                              Pore Size                                                                             Gurley Com-                                   #     (%)      (μm)  Loss (%)                                                                              (secs) ments                                  ______________________________________                                        13A   82.2%    0.479    --      9.9                                           13B   76.3%    0.427    12%     12.6   No pore                                                                       blockage                               13C   78.5%    0.213    --      29.0                                          13D   74.5%    0.098    54%     121.0  Some pore                                                                     blockage                               13E   76.3%    0.149    --      53.4                                          13F   68.9%    0.102    33%     184.3  Some pore                                                                     blockage                               13G   57.8%    0.101    --      269.7                                         13H   47.5%    <<0.1    ˜100%                                                                           >>1K   Complete                                                                      surface                                                                       pore                                                                          blockage                               ______________________________________                                    

Example 14

The procedure of Example 1 was used to prepare a hydrophilic PVA shellmembrane from a microporous PE membrane having a pore size of 0.259microns and a 77 percent porosity, prepared according to Example 23 ofU.S. Pat. No. 4,539,256, except that a 4.7 percent (w/v)solution ofsyndiotactic PVTFA in cyclohexanone was used, and the two zones of theoven were set to 38° C. and 106° C. respectively. The higher viscosityof the cyclohexanone PVTFA solutions relative to the viscosity of theacetone PVTFA solutions coupled with the relatively high oventemperatures used to dry the treated membranes resulted in the formationof an integral pore-blocking skin on the membrane surface. The presenceof the skin was demonstrated by an effectively infinite Gurley airpermeability value and by SEM analysis.

Example 15

Samples of hydrophilic microporous membranes were prepared according toExample 1 and were subjected to extractions by highly polar organicsolvents to demonstrate the ability of the PVA shell to resist wash-out.The initial PVA add-on was 9.1 weight percent of the untreatedhydrophobic microporous membrane. The samples were weighed and thensoaked for 1.5 hours in the indicated solvents, followed by four rinsesof water to remove the solvent. The samples were dried, reweighed and apercentage weight loss for the hydrophilic membrane calculated by weightdifferential.

Samples exposed to each of the above solvents remained hydrophilic tovarying degrees. Dimethyl formamide (DMF) caused the greatest percentageweight loss of the PVA shell, perhaps because the DMF dissolves the PVAcrystallites (c.f. FIG. 3 ). Thus, while the hydrophilic polymericstructure produced according to the present invention is resistant towashout by DMF at least after continuous exposure for up to 1.5 hours,care should be taken to select a polymeric structure which does not alsodegrade or dissolve during exposure to the highly polar solvent.

                  TABLE 8                                                         ______________________________________                                                                          Polyvinyl                                                                     Alcohol                                     Ex-                  Sample Percent                                                                             Shell Percent                               ample Solvent        Weight Loss  Weight Loss                                 ______________________________________                                        15A   Dimethylsulfoxide                                                                            0.7          8.0                                               [DMSO]                                                                  15B   Dimethylformamide                                                                            3.7          40.5                                              [DMF]                                                                   15C   Glycerol [GLY] 0.5          5.5                                         15D   Ethylene Glycol                                                                              0.2          2.2                                               [EtGLY]                                                                 ______________________________________                                    

Example 16

An inherently hydrophilic microporous Nylon 6,6 membrane, rated with a0.45 micron pore size, obtained from Schleicher & Schuell of Keene,N.H., was saturation-covered with a 4 percent w/v acetone solution ofsyndiotactic PVTFA following the procedure of Example 2. The resultingPVTFA envelopment of the internal and external surfaces of the membranedid not block the pores, but due to the hydrophobicity of PVTFA, theNylon 6,6 membrane was rendered hydrophobic. Upon reaction with theammonia vapor of ammonium hydroxide, as in Example 2, the PVA shellmembrane again became hydrophilic as demonstrated by spontaneous andnearly instantaneous wetting with water. Characterization data, beforeand after this treatment are tabulated in Table 9, below. This exampledemonstrated the use of the present treatment to provide hydroxylfunctional groups to the surface of a hydrophilic membrane withoutsignificantly blocking the pores or reducing the hydrophilicity.

                  TABLE 9                                                         ______________________________________                                                                   Pore                                                                          Size                                               Example                                                                              Condition Pore Size Loss  Gurley Porosity                              ______________________________________                                        16A    Uncovered 0.771μ --    14 sec 61.7%                                 16B    PVA Shell 0.740μ 5%    24 sec 60.4%                                 ______________________________________                                    

Example 17

A piece of Gore-Tex™ poly(tetrafluoroethylene) membrane, manufactured byW. L. Gore and Associates, Inc. of Elkton, Md. was saturated with a 5percent w/v acetone solution of syndiotactic PVTFA prepared according toExample 1 using a #14 wire-wound bar to spread the solution. This samplewas allowed to dry at room temperature in a ventilation hood to producea PVTFA shell on the external and internal surfaces of the membrane,without causing pore blockage or PVTFA skin formation, as shown by SEMexamination. The sample was reacted with vaporous ammonia as in Example1 to yield a highly hydrophilic membrane, as shown by beingspontaneously and nearly instantaneously wetted with water.

Example 18

A piece of a calendered spunbonded PE web, commercially available underthe trademark "Tyvek T-984", from E. I. DuPont of Wilmington, Del.,having an average Gurley air flow of 3.1 sec per 50 cm³ of air, wassaturation-covered with a 4 percent w/v acetone solution of syndiotacticPVTFA according to the procedure of Example 2. After drying and reactingin-situ with ammonia vapor, the PVA shell web was hydrophilic as judgedby being spontaneous and nearly instant wettability with water. The webwas still through-porous, since water would pass through the web afterthe hydrophilization and exhibited a Gurley value of 9.8 sec per 50 ccof air.

Example 19

A polypropylene melt-blown web, was made according to the proceduredescribed in Wente, Van A., "Superfine Thermoplastic Fibers" inEngineering Chemistry, Vol. 48, p. 1342 et. seq. (1956), or in ReportNo. 4364 of the Naval Research Laboratories, published May 25, 1954,entitled "Manufacture of Superfine Organic Fibers", by Wente, V. A.;Boone, C. D.; and Fluharty, E. L., the disclosures of which areincorporated by reference herein. It was covered with a 6 percent w/vacetone solution of syndiotactic PVTFA according to the procedure ofExample 2. After drying and in-situ reaction with ammonia vapor, thisPVA shell melt-blown web was hydrophilic as demonstrated by spontaneousand nearly instant wetting with water. The resistance of thishydrophilic treatment to washout was demonstrated by 16 repeatedsoak/squeeze/dry cycles with pure water, resulting in a melt-blown webthat was still as hydrophilic as it was initially, as shown byspontaneous and nearly instant wettability with water.

Example 20

A polypropylene woven fabric, obtained from the Arthur Kahn Co., of NewYork, N.Y., which was hydrophobic (i.e., a drop of water did notpenetrate the fabric when it was placed on the fabric gently) wascovered with a 4 percent w/v solution of syndiotactic PVTFA in acetoneusing the method of Example 2. (The weave of the starting fabric wascoarse enough, however, to allow water to penetrate if any pressure wasapplied to the drop.) This resulted in a shell of PVTFA enveloping thesurface of the fabric's fibers. Upon reaction of the PVTFA coveredfabric with the ammonia vapor of ammonium hydroxide, as in Example 2,the fabric having a PVA shell about its surfaces became hydrophilic asdemonstrated by spontaneous and nearly instant wetting with water.

Example 21

In order to show the availability of the hydroxyl functional groups ofthe hydrophilic shell towards chemical derivatization, the hydrophilicmembrane from Example 1 was reacted with an acid chloride. Enoughsebacyl chloride was added to a glass vessel to cover a piece of thevacuum dried membrane placed in the vessel. These were allowed to reactfor 1/2 hour at room temperature. The sample was rinsed in1,1,1-trichloroethane to remove excess acid chloride. Infraredspectroscopy of the reacted membrane showed a new carbonyl absorption at1737⁻¹ cm and a decrease in the hydroxyl absorption at 3300⁻¹ cm, whichindicated that esterification of the hydroxyl group had occurred.

Example 22

A microporous polypropylene (PP) membrane, made by thermally inducedphase separation as disclosed in U.S. Pat. No. 4,726,989 (Mrozinski),Example 9, having a Bubble Point maximum pore size of 0.65 μm, anaverage Gurley of 6.4 sec per 50 cc of air and a thickness of 0.82 mmwas extrusion saturated with a 4.5 percent (w/v) solution ofsyndiotactic PVTFA according to procedure of Example 1 except that themembrane was dried for about 45 seconds. The resulting treated membranehad a PVTFA add-on of 25.6 percent. A PVA shell membrane was prepared byhydrolyzing the PVTFA treated membrane in a stream of anhydrous ammoniaaccording to the procedure of Example 9, followed by hydration withdeionized water and drying at room temperature for about four (4)minutes. The PVA shell membrane had a Bubble Point pore size of 0.575 μmand was hydrophilic as demonstrated by it being spontaneously and nearlyinstantly wetted with water.

The filtration performance of the PVA shell membrane, the untreated PPmicroporous membrane and a commercially available microporous membrane,namely a 0.22 μm Durapore™ polyvinylidene difluoride microporousmembrane (available from Millipore Corp, Bedford, Mass.) were comparedby measuring the turbidity of the filtrate obtained when each membranewas challenged with a submicron sized suspension. A Hach RatioTurbidimeter (Model 18900), available from Hach Instruments (FortCollins, Co.) was used to determine filtrate turbidity. The challengesuspension was prepared by adding six drops of a Fastek 0.22 μm sizedlatex sphere suspension (formerly available from Eastman Kodak) to 1600ml of ultrapure water which had a turbidity of 0.08 NephelometricTurbidity Units (NTU) to produce a suspension having a turbidity of 117NTU. A 47 mm diameter disk of the test membrane was placed on thesupport plate of a Gelman Magnet Filter Holder, the top of the filterholder installed and the filter holder placed on a vacuum filtrationflask. A laboratory vacuum of approximately 56 cm Hg was applied to thefilter flask and the average time required to collect 100 ml of filtratefor each membrane filter and the turbidity of each filtrate sample asmeasured on the Hath Turbidimeter are reported in Table 10.

                  TABLE 10                                                        ______________________________________                                        Membrane       Time/100 ml Filtrate                                                                           Turbidity                                     Sample         (seconds)        (NTU)                                         ______________________________________                                        PP Membrane     90*             1.62                                          PVA Shell Membrane                                                                           195              0.325                                         Durapore Membrane                                                                            155              5.4                                           ______________________________________                                         *There was no flow through the untreated membrane until it had been wet       with isopropanol.                                                        

The data in Table 10 shows that the microporous membrane filter based onthe PVA shell membrane of the present invention has significantly betterparticle retention properties than the untreated membrane as isevidenced by the lower turbidity of the filtrate obtained using the PVAshell membrane. Reasonably close filtration rates between the PVA shellmembrane and the Durapore membrane implies that the two membranes haveporosities which are quite similar but the lower turbidity of thefiltrate obtained with the PVA shell membrane suggests that it is likelythat the PVA shell membrane has either a smaller pore size or a highertortuosity as compared to the Durapore membrane and consequently it canprovide superior filtration performance.

Microporous membrane filters known to provide absolute control overbacterial contaminants above a critical size can be used to "coldpasteurize" or sterilize thermally sensitive aqueous fluids. Severaltechniques are used to validate the retentive efficiency, compatibility,and life expectancy of filters with an absolute pore-size rating above0.02 μm. While a rigorous validation of filter efficiency requires theuse of several techniques, an indication of filter efficiency can beprovided by challenging the filter with 0.22 μm latex particle andcomparing the concentration of spheres up- and downstream of the filterby means of turbidimetric analysis (see Goldsmith et. al.,Pharmaceutical Manufacturing, November 1985. pp 31-37). The data inTable 10 suggests that the PVA shell membranes of the present inventionhave the potential of realizing an "absolute" rating for control ofparticles larger than 0.22 μm and thus, might be suitable forsterilization of aqueous fluids.

Example 23

Diffusion studies of mannitol through hydrophobic PE microporousmembranes and hydrophobic PE microporous membranes rendered hydrophilicby a syndiotactic PVA shell were conducted to measure any difference influx rates of water soluble mannitol (simulating therapeutic agents)therethrough. Radiolabeled 3H-mannitol was studied using standarddiffusion cell methodology. A "Valia-Chien" side by side diffusion cell(as described in "Drug Development and Industrial Pharmacy" 1985 No. 11,pg. 1195, the disclosure of which is incorporated by reference, andcommercially available from Crown Glass of Somerville, N.J.) was usedwith a PE membrane, prepared according to Example 23 of U.S. Pat. No.4,539,256 (Shipman) and a PVA shell PE membrane, prepared according toExample 1 above. Each membrane was placed between the donor andreceiving chambers of the diffusion cells. Three milliliters of HepesBuffer at a pH of 7.0, was pipetted into each chamber and equilibratedto 32° C. At t=0, the radiolabeled 3H-mannitol samples (commerciallyavailable from NEN Research Products, a DuPont company, of Boston,Mass.) were added to the donor chamber. Aliquots were removed at hourlyintervals and analyzed by standard liquid scintillation countingmethods.

The permeability coefficient, P, was obtained through a plot ofcumulative permeant in the receiver compartment per unit area perdriving force vs. time. The expression which was plotted was: ##EQU2##where C_(r) is concentration in the receiver cell, t is time in hours,V_(r) is volume in the receiver cell, SM_(r) is the sum of thepreviously sampled mass in the receiver cell, C_(d) is concentration inthe donor cell, g is activity coefficient of 3H mannitol in an activityratio between receiving and donor cell, and A is area of diffusion.G_(r) /g_(d) was assumed to be 1.

The results showed a permeability coefficient of 0.0005 cm/hr for thehydrophobic PE microporous membrane. The permeability coefficientmeasured for the PVA shell PE microporous membrane was 1.856 cm/hr.

Example 24

The procedure of Example 239 was replicated, except that a 50:50ethanol/water solution was used in the diffusion chamber in place of theHepes Buffer when experimenting with the PE microporous membrane andwater was used in the diffusion chamber in place of the HEPES Bufferwhen experimenting with the PVA shell PE microporous membrane. Theaverage of 4 tests on each type of membrane are shown in Table 15.

                  TABLE 11                                                        ______________________________________                                                        Permeability                                                                  Coeff.     Gurley                                                                              Pore Size                                                                            Porosity                              Ex.   Membrane  (cm/hr)    (sec) (μm)                                                                              (%)                                   ______________________________________                                        24A   PE        0.32       91    0.11   60                                    24B   PVA/PE    2.55       20    0.68   72                                    ______________________________________                                    

Example 25

The procedure of Example 239 was replicated, except that a H³ -Mannitolwas replaced with a 0.1M solution of Triprolidine HCl (commerciallyavailable from Burroughs-Welcome of Research Triangle Park, N.C.) inHEPES Buffer. The results showed a permeability coefficient of 0.0005cm/hr for the hydrophobic PE microporous membrane. The permeabilitycoefficient measured for the PVA shell PE microporous membrane was0.9162 cm/hr.

Neither the embodiments of the invention nor the examples describedabove limit the scope of this invention.

What is claimed is:
 1. A microporous drug delivery membrane having ahydrophilic, polymeric shell, comprising:a supporting structure having acomplex geometric configuration and surfaces about said structure and anextremely thin, self-interlocking, tactic, hydrophilic poly(vinylalcohol) shell enveloping at least a portion of said surfaces whilesubstantially retaining said complex geometric configuration.
 2. Themembrane according to claim 1, wherein said membrane is a polyolefinrendered hydrophilic and having pores of from about 0.01 μm to about 20μm.
 3. The membrane according to claim 1, wherein said membrane has acomplex geometric configuration and said shell substantially retainssaid complex geometric configuration of said membrane.
 4. The membraneaccording to claim 1, wherein said shell is between about an average of10 monolayers to about an average of 4000 monolayers thick on saidsurfaces.
 5. The membrane according to claim 1, wherein said shell issubstantially insoluble in solvents having a solubility parameterdifferential to a solubility parameter of poly(vinyl alcohol) of greaterthan about 0.4.
 6. The membrane according to claim 1, wherein pores ofsaid structure are larger than the mean free path of flowing moleculesof the drug.
 7. The membrane according to claim 1, wherein saidpolymeric membrane is hydrophobic.
 8. The membrane according to claim 1,wherein said shell has a sufficient pore wetting surface energy topermit spontaneous wetting of the drug delivery membrane with watercontaining a drug and an optimal excipient.
 9. A drug delivery device,comprising: a hypoallergenic pressure sensitive adhesive layer, atherapeutic agent, and a membrane of claim 1 contacting said adhesivelayer and in communication with said therapeutic agent.
 10. The drugdelivery device according to claim 9, wherein said membrane is apolyolefin rendered hydrophilic and has pores of from about 0.01 μm toabout 20 μm.
 11. The drug delivery device according to claim 9, whereinsaid shell is between about an average of 10 monolayers to about anaverage of 4000 monolayers thick on said surfaces.
 12. The drug deliverydevice according to claim 9, wherein said shell is substantiallyinsoluble in solvents having a solubility parameter differential to asolubility parameter of poly(vinyl alcohol)of greater than about 0.4.13. The drug delivery device according to claim 9, wherein pores of saidstructure are larger than the mean free path of flowing molecules of thedrug.
 14. The drug delivery device according to claim 9, wherein saidmembrane is between said therapeutic agent and said pressure sensitiveadhesive layer.
 15. The drug delivery device according to claim 9,wherein said membrane comprises a porous depot for said therapeuticagent.
 16. The drug delivery device according to claim 9, wherein saidtransdermal delivery device further comprises an excipient incommunication with said therapeutic agent and said membrane.
 17. A drugdelivery device, comprising: a hypoallergenic pressure sensitiveadhesive layer, a therapeutic agent, optionally an excipient in areservoir, and a membrane according to claim 1 contacting said adhesivelayer and contacting the reservoir.
 18. The drug delivery deviceaccording to claim 17, wherein said membrane is between said therapeuticagent and said pressure sensitive adhesive layer.
 19. The drug deliverydevice according to claim 17, wherein said pressure sensitive adhesivelayer is absent from a pathway from said reservoir to skin of a patient.20. The drug delivery device according to claim 9, wherein the membraneis hydrated for use in iontophoresis.